Dihydronorthebainone and dihydronororipavinone compounds and corresponding enol lower alkyl ethers



3,468,891 DIHYDRONORTHEBAINONE AND DIHYDRO- NORORIPAVINONE COMPOUNDS AND COR- RESPONDING ENOL LOWER ALKYL ETHERS James Richard Bartels-Keith, Brookline, Mass., and

Derek William Hills, Welwyn Garden City, England, assignors to Smith Kline & French Laboratories, Philadelphia, Pa., a corporation of Pennsylvania No Drawing. Filed July 21, 1967, Ser. No. 654,958 Claims priority, application Great Britain, July 29, 1966, 34,301/66 Int. Cl. A61k 27/00; C0711 43/28 US. Cl. 260-285 Claims ABSTRACT OF THE DISCLOSURE Dihydronorthebainone and dihydronororipavinone compounds and the corresponding enol lower alkyl ethers which have an unsaturated group or a cycloalkylmethyl group as an N-substituent are prepared by reduction of the corresponding dihydronorthebaines or dihydronororipavines or by N-substitution of the corresponding N-unsubstituted dihydronorthebainone or dihydronororipavinone compounds or the enol lower alkyl ethers. These compounds have analgesic activity.

Formula I Fl N l B 0B3 0 4 in which:

R1 is i CH2-C=C in which R R and R, are hydrogen, methyl or halogen, for example allyl, 2,3-dichloroallyl or 3,3-dimethylallyl; propargyl or cycloalkylmethyl such as cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl or eyclohexylmethyl;

R is hydrogen, lower alkyl preferably methyl, acyl such as a lower alkanoyl (for example acetyl, propionyl, butyryl or isobutyryl), benzoyl, nicotinoyl or isonicotinoyl;

R is hydrogen or acyl such as lower alkanoyl; and

R is hydrogen or lower alkyl, preferably methyl.

Preferred compounds of this invention are represented by Formula I when:

nited States Patent 0 "ice in which R R and R are hydrogen, methyl or chloro or cycloalkylmethyl, preferably cyclopropylmethyl or cyclobutylmethyl; R is hydrogen or methyl; R is hydrogen or lower alkanoyl; and R is methyl.

Exemplary of advantageous compounds of this invention are N cyclopropylmethyl-A -dihydronorthebainone enol methyl ether, N-cyclopropylmethyl -A -dihydronororipavinone enol methyl ether, N cyclobutylmethyl A dihydronorthebainone enol methyl ether, N-3,3-dimethylallyl-A -dihydronorthebainone enol methyl ether and N-allyl-A -dihydronorthebainone enol methyl ether and the pharmaceutically acceptable acid addition salts thereof.

The terms lower alkyl and lower alkanoyl are used herein as meaning groups containing from 1 to 4 carbon atoms inclusive.

Although included within the scope of the invention are the pharmaceutically acceptable acid addition salts of the compounds of Formula I.

It will be appreciated by those skilled in the art that in those compounds of Formula I in which R, is hydrogen keto-enol tautomerism is possible. In such compounds the keto form is believed to be predominant.

The compounds of Formula I in which R is hydrogen may be prepared either (a) by hydrogenation (reduction) of a compound of the general formula:

Formula II Formula III III N I l R 0 OH OR:

in which R, has the same meaning as in Formula I and R is hydrogen or lower alkyl, with a reactant which will give the desired R substituent on the nitrogen atom, for example R -X in which X is halide.

The compounds of Formula III, which are also objects of this invention, may be obtained by the method (a) described above, R being hydrogen.

The compounds of Formulas II and III may be prepared from the known starting compounds dihydromorphinone, dihydronormorphinone, dihydrocodeinone 0r dihydronorcodeinone by suitable synthetic routes. Procedures for preparing the starting materials of Formula II and some of these compounds are described in US. Patent 3,299,072.

The compounds of Formula I in which R and/or R are acyl are prepared by acylation of the corresponding compounds in which R and/or R are hydrogen, using for example the appropriate equivalent amount of an acyl halide or acid anhydride generally in the presence of an acid binding agent, for example pyridine and, where appropriate, separating acrylated products by fractional crystallization and/or chromatography.

The compounds of Formula I in which R; is hydrogen may also be prepared from the corresponding compounds of Formula I in which R, is a lower alkyl group by acid hydrolysis using, for example, hydrobromic acid.

The pharmaceutically acceptable acid addition salts of the compounds of Formula I may be prepared by reacting the base with an acid which will give the required salt, for example by treating the base in an organic solvent with an equivalent amount of the desired acid.

At the present time the position of the double bond in the non-aromatic unsaturated ring of the compounds of Formulas I, II and HI are not known for certain, although in the compounds of Formulas I and III it is thought to be in the C -C position while in the compounds of Formula II it is thought to be in the C -C position. However for the sake of simplicity in describing the present invention it will be assumed that the double bond is in position 5,6 in the compounds of Formulas I and III and in the position 6,7 in the compounds of Formula II.

It will be appreciated that for therapeutic use the compounds of the invention will generally be administered as a pharmaceutical composition comprising a compound of the invention as an essential active ingredient in association with a pharmaceutical carrier of a kind normally employed in the production of drugs ready for administration. Advantageously the composition is made up in a dosage unit fonn suitable for the desired mode of administration. Thus for oral administration the dosage unit may be, for example, a tablet, capsule, pill or troche, while for parenteral administration the dosage unit may be, for example, an ampule or the like container having disposed therein an injectable substantially isotonic saline solution of the active compound in pyrogen free distilled water.

The following examples illustrate the invention and are not intended to restrict the scope thereof.

EXAMPLE 1 N-cyclopropylmethyl-A -dihydronorthebaine (1.5 g.), obtained in the manner described in Example 3 of U.S. 3,299,072, is dissolved in dry tetrahydrofuran (30 ml.) in a 250 ml. flask fitted with a reflux condenser cooled by solid carbon dioxide and the flask is cooled to 80 C. with a bath of solid carbon dioxide/acetone. Liquid ammonia (90 ml.) is then added to the resulting solution by distillation into it. The temperature of the resulting reaction mixture is then allowed to rise until the ammonia refluxes gently. Metallic sodium is then added in small (about 50 mg.) pieces as soon as the previous piece has dissolved. When the reaction mixture becomes permanently blue, which occurs when 0.5 g. of sodium has been added, ammonium chloride (1 g.) is added, the reflux condenser is removed and the ammonia is allowed to evaporate at room temperature. To the remaining reaction mixture (a milky fluid) are added water (30 ml.) and brine (saturated sodium chloride solution, 100 ml.) and the mixture is then extracted with benzene (50 ml.). The separated benzene solution is dried with anhydrous magnesium sulphate, filtered and evaporated under reduced pressure leaving a White foam. On adding diethyl ether to the foam, N-cyclopropylmethyl-A dihydronorthebai none enol methyl ether is obtained in colorless needle clusters having a M.P. of 95-96 C.

A portion (1 g.) of this product is dissolved in dry diethyl ether (10 ml.) and a saturated solution of salicylic acid in dry diethyl ether is added dropwise until no further precipitation occurs. The solid is separated by 4 filtration and recrystallized from 95% ethanol (rectified spirit) to give the salicylate salt as large colorless prisms having a M.P. of 164.5165.5 C.

EXAMPLE 2 N-cyclopropylmethyl-A -dihydronororipavine (2.2 g.), obtained in the manner described in Example 5 of U.S. 3,299,072, is dissolved in dry tetrahydrofuran (30 ml.) following which the procedure described in the foregoing Example 1 is followed. The total quantity of sodium required is 0.48 g. and when the ammonia has evaporated a brown solution remains which is extracted as described in Example 1 so as to obtain N-cyclopropylmethyl-A -dihydronororipavinone enol methyl ether.

A sample of the above prepared product (1.4 g.) is added to one equivalent of salicylic acid dissolved in the minimum quantity of ethanol and warmed to 50 C. until a clear solution is obtained. 0n standing, a crystalline product forms which is filtered off and recrystallized from ethanol to give the salicylate salt of N-cyclopropyhnethyl- A -dihydronororipavinone enol methyl ether as cream colored needles having a M.P. of 206-208 C. (decomp).

EXAMPLE 3 N-cyclobutylmethyl-A -dihydronorthebaine (3 g.) is dissolved in dry tetrahydrofuran (30 ml.) in a flask fitted with a reflux condenser cooled by solid carbon dioxide. The resulting solution was stirred in a bath of solid carbon dioxide/acetone at C. under dry nitrogen. Liquid ammonia ml.) is then distilled into the solution. The carbon dioxide/acetone bath is removed and the ammonia is allowed to refiux gently. Metallic sodium (1.0 g.) is then added portionwise in 50 mg. pieces until the reaction mixture becomes permanently blue. Solid ammonium chloride (1 g.) is added With the result that the reaction mixture becomes colorless. The ammonia is then evaporated and to the remaining reaction mixture are added saturated sodium chloride solution (50 ml.) and water (50 ml.). The resulting mixture is then extracted with benzene and the benzene extracts are dried over anhydrous magnesium sulphate, filtered and then evaporated to give a colorless glass-like solid. On dissolving this glass-like solid in ether, colorless needles of N-cyclobutylmethyl-A -dihydronorthebainone enol methyl ether are deposited, M.P. 104l05 C.

The N-cyclobutyImethyl-A -dihydronorthebaine starting material is prepared in the following manner:

Stage 1.Dihydronorcodeinone (15 g.) is dissolved in dioxane (150 ml.) and water (15 ml. )and anhydrous potassium carbonate (15 g.) added. The resulting mixture is stirred and cyclobutyl carbonyl chloride (10.5 g.) is added dropwise during 30 minutes. Stirring is continued for a further three hours and the reaction mixture is then poured into water (500 ml.) and the resulting suspension adjusted to a pH of 11.0 by addition of 2 N sodium hydroxide solution. This suspension is then extracted with chloroform (1X 200 ml.;+2 ml.) and the combined chloroform extracts are successively washed with N hydrochloric acid (150 ml.) and water (100 ml.) and then dried over anhydrous magnesium sulphate. Filtration and evaporation of the filtrate under reduced pressure gives N-cyclobutylcarbonyldihydronorcodeinone as a white foam.

Stage 2.Metallic sodium (0.855 g.) is added to a mixture of dry tertiary butyl alcohol (152 ml.) and dry methanol (1 ml.) and the mixture heated in an atmosphere of dry nitrogen until solution of the metal is complete. After cooling to room temperature a further quantity of tertiary butyl alcohol (76 ml.) is added and stirred (still in dry nitrogen atmosphere) 'while N-cyclobutylcarbonyldihydronorcodeinone (11.79 g.), dissolved in dry tertiary butyl alcohol ml.), is added in a steady stream resulting in a clear yellow solution. To this solution is added a solution of dimethyl sulphate (4.3 g.) in dry tertiary butyl alcohol (25 ml.) dropwise and with stirring during one hour and the resulting mixture is then heated to refluxing temperature for a further two hours.

The solvent is then removed under reduced pressure and the residue is stirred for minutes with dilute aqueous ammonia ml. of 0.880 ammonia diluted to 500 ml. with Water) and then extracted with benzene (2X 150 ml.+1 100 ml.). The combined benzene extracts are washed with Water (100 ml.), dried with anhydrous magnesium sulphate, filtered and evaporated under reduced pressure to dryness. The residue is redissolved in dry benzene and chromatographed on activated alumina, type H (150 g.). Elution with benzene and evaporation of the eluate under reduced pressure gives a White foam which crystallizes on addition of a little diethyl ether and has a M.P. of 140-l41 C. This material is N-cyclobutylcarbonyl-A -dihydronorthebaine.

Stage 3.To a suspension of lithium aluminium hydride (2.5 g.) in dry tetrahydrofuran (100 ml.) is added a solution of the above N-cyclobutylcarbonyl-A -dihydronorthebaine (5 g.) in dry tetrahydrofuran (125 ml.). The mixture is heated to reflux for three hours in an atmosphere of dry nitrogen and then cooled to 0 C. and the residual complex and excess lithium aluminum hydride is decomposed by the dropwise addition of a mixture of tetrahydrofuran (20 ml.) and Water (2.5 ml.) followed by 15% sodium hydroxide (2.5 ml.) and water (7.5 ml.) in that order. The precipitate is filtered oil and washed with diethyl ether (200 ml.). The filtrate and washings are combined, dried with anhydrous magnesium sulphate, filtered and evaporated under reduced pressure. The residue is a colorless gum which is dissolved in a minimum quantity of warm diethyl ether and on standing forms a crystalline precipitate of N-cyclobutylmethyl-M-dihydronorthebaine, M.P. 135137 C.

EXAMPLE 4 N-3,3-dimethylallyl-A -dihydronordiebaine (4.96 g.) is reduced with metallic sodium in liquid ammonia in a manner similar to that described in Example 1 to give N-3,3-dimethylallyl-M-dihydronorthebainone enol methyl ether as small colorless needles of M.P. 119-l20 C.

The N-3,3-dimethylallyl-A -dihydronorthebaine starting material is prepared in the following manner:

Stage 1.A mixture of dihydronorcodeinone (12.15 g.), 1-bromo-3 methyl-2-butene (6.7 g.), sodium bicarbonate (5.37 g.) and N,N-dimethylformamide (110 m1.) is stirred at refluxing temperature for five hours. The reaction mixture is then cooled to room temperature and filtered; the residual solid on the filter is washed with ethanol. The combined filtrate and washings are evaporated under reduced pressure leaving a residue of a dark brown oil. This oil is dissolved in 2 N hydrochloric acid (100 ml.) and the solution washed with diethyl ether (3X 100 ml.). The aqueous phase is then made strongly alkaline by the addition of 0.880 ammonia solution and extracted with diethyl ether (3X 100 ml.). The combined ethereal extracts are dried over anhydrous magnesium sulphate and evaporated giving crude N-3,3-dimethylallyl dihydronorcodeinone (11.88 g.) as a brown glassy solid. This is purified by dissolving in ethanol (75 ml.) and adding the resulting solution dropwise with shaking to a solution of tartaric acid (5.1 g.) in ethanol (50 ml.). On standing, cream colored needles (16.7 g.) of M.P. 119-120 C. separate and are filtered olf. These are dissolved in a minimum of cold Water and the solution basified with 0.880 ammonia solution when a yellow sticky solid separates which is then extracted with diethyl ether (3 X 100 ml.). The combined ethereal extracts are dried with anhydrous magnesium sulphate, filtered and evapo rated under reduced pressure giving pure N-3,3-dimethylallyl-dihydronorcodeinone as a colorless foam.

Stage 2.The compound (10 g.) prepared in Stage 1 is methylated in exactly the manner described in Example 3, Stage 2 to provide N-3,3-dimethylallyl-A -dihydronorthebaine as a colorless foam.

6 EXAMPLE 5 Nellyl-M-dihydronorthebaine (1.04 g.), obtained in the manner described in Example 11 of U8. 3,299,072, is reduced by metallic sodium in liquid ammonia in the manner described in Example 1 to give N-allyl-A -dihydronorthebainone enol methyl ether as a colorless foam.

This free base is converted into its salicylate salt by dissolving it in dry diethyl ether (10 ml.) and adding to the solution so formed a solution of salicylic acid (0.49 g.) in diethyl ether (10 ml.) to form a white solid precipitate, which is filtered off and recrystallized from an ethanol/water mixture to give colorless rhombic rods of N-allyl-A -dihydronorthebainone enol methyl ether salicylate, M.P. 142-143 C.

EXAMPLE 6 N-allyl-A -dihydronorthebainone enol methyl ether (1.4 g.), prepared in the manner described in Example 5, is dissolved in ethanol (10 ml.) and 3.7 N hydrobromic acid (1.14 ml.) is added, the resulting mixture then being heated for one hour at 50-60 C. Evaporation of the solvent under reduced pressure gives a yellowish brown solid which is then recrystallized from ethanol to give N- allyl-dihydronorthebainone hydrobromide as buff colored rods, M.P. 234236 C.

EXAMPLE 7 N cyclopropylmethyl A dihydronorthebainone enol methyl ether (1.0 g.), prepared in the manner described in Example 1, is mixed with acetic anhydride (1.0 ml.) and dry pyridine -(5 ml.) and the resulting mixture is stirred for 20 hours at room temperature and then poured into water (10 ml.). Saturated aqueous sodium bicarbonate solution (40 ml.) is added and the resulting mixture is extracted with diethyl ether (3X 50 ml.). The combined ethereal extracts are dried with anhydrous magnesium sulphate, filtered and evaporated under reduced pressure leaving a residue of a colorless foam (1.0 g.). The foam is dissolved in diethyl ether (20 ml.) and a solution of salicyclic acid (0.35 g.) in diethyl ether (20 ml.) is added. A white solid precipitates which is filtered off and recrystallized from an ethanol/Water mixture to give colorless rhombic rods of O-acetyl-N-cyclopropylmethyl-A -dihydronorthebainone enol methyl ether, M.P. 161 C.

Similarly, using propionyl chloride, butyryl chloride and isobutyryl chloride in the above procedure, the products are, respectively, O-propionyl-N-cyclopropylmethyl- N-dihydronorthebainone enol methyl ether, O-butyryl-N- cyclopropylmethyl A dihydronorthebainone enol methyl ether and Oisobutyryl-N-cyclopropy1rnethyl-A dihydronorthebainone enol methyl ether.

EXAMPLE 8 Using N cyclopentylmethyl A dihydronororipavine, prepared as in Example 7 of US. 3,299,072, in place of N cyclopropylmethyl A dihydronororipavine in the procedure of Example 2 gives N-cyclopentylmethyl-A -dihydronororipavinone enol methyl ether.

A portion of the above prepared product in ethanol is treated with an equimolar amount of hydrobromic acid in ethanol. The resulting solution is treated with benzene, then concentrated in vacuo. Diethyl ether is added. Filtering gives the hydrobromide salt of N-cyclopentylmethyl- M-dihydronororipavinone enol methyl ether.

Similarly, using N cyclohexylmethyl A dihydronororipavine, prepared as in Example 7 of US. 3,299,072, N cyclohexylmethyl A dihydronororipavinone enol methyl ether and the hydrobromide salt thereof are obtained.

EXAMPLE 9 N -dihydronorthebaine (4.05 g.), obtained in the manner described in Example 4 of U.S. 3,299,072, is reduced with metallic sodium in liquid ammonia in the manner described in Example 1 to give A -dihydronorthebainone enol methyl ether as colorless rhombic plates, MP. 210- 211 C.

A mixture of M-dihydronorthebainone enol methyl ether (3.0 g.) and propargyl chloride (0.75 g.) in 50 ml. of ethanol containing 1.0 g. of sodium bicarbonate is heated at reflux with stirring for 12 hours. The mixture is then concentrated in vacuo. The residue is washed with water and extracted with benzene. The benzene extract is concentrated in vacuo. Adding diethyl ether and filtering gives N-propargyl-n -dihydronorthebainone enol methyl ether.

By the same procedure, using the following in place of propargyl chloride:

3,3-dichloroallyl bromide 2,3-dichloroallyl bromide the products are, respectively:

N-3,3-dichloroallyl-A -dihydrothebainone enol methyl ether N-2,3-dichloroallyl-M-dihydrothebainone enol methyl ether.

EXAMPLE N cyclopropylmethyl A dihydronororipavinone enol methyl ether (3.4 g.), prepared in the manner described in Example 2, 1.57 g. of nicotinoyl chloride and ml. of dry pyridine are stirred at room temperature for 24 hours. The mixture is then poured into water. Saturated aqueous sodium bicarbonate solution (100 m1.) is added and the resulting mixture is extracted with diethyl ether. The ether extracts are dried with anhydrous magnesium sulfate, filtered and concentrated under re duced pressure. The residue is dissolved in diethyl ether and a solution of salicylic acid in diethyl ether is added. The solid material is filtered off and recrystallized from aqueous ethanol to give 3-O-nicotinoyl-N-cyclopropylmethyl-A -dihydronororipavinone enol methyl ether.

Similarly, using an equivalent amount of acetyl chloride in the above procedure, 3-O-acetyl-N-cyclopropylmethyl-M-dihydronororipavinone enol methyl ether is obtained.

By the same procedure using propionyl chloride, butyryl chloride, isobutyryl chloride, benzoyl chloride and isonicotinoyl chloride the following products are obtained, respectively:

| R20 0R3 CR4 and pharmaceutically acceptable acid addition salts thereof, in which:

8 R1 is in which R R and R are hydrogen, methyl or halogen; propargyl or cycloalkylmethyl;

R is hydrogen, lower alkyl having 1 to 4 carbon atoms, lower alkanoyl, benzoyl, nicotinoyl or isonicotinoyl;

R is hydrogen or lower alkanoyl; and

R is hydrogen or lower alkyl having 1 to 4 carbon atoms.

2. A compound according to claim 1 in which R, is cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl or cyclohexylmethyl.

3. A compound according to claim 1 in which R is allyl, 2,3-dichloroallyl or 3,3-dimethylallyl.

4. A compound according to claim 1 in which R is cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, allyl, 2,3-dichloroallyl or 3,3-dimethylallyl; R is hydrogen or methyl; R is hydrogen and R is methyl.

5. A compound according to claim 1 in which R is cyclopropylmethyl, R is methyl, R is hydrogen and R is methyl, said compound being N cyclopropylmethyl- A dihydronorthebainone enol methyl ether, and pharmaceutically acceptable acid addition salts thereof.

6. A compound according to claim 1 in which R, is cyclopropylmethyl, R and R are hydrogen and R is methyl, said compound being N cyc1opropylmethyl-A dihydronororipavinone enol methyl ether, and pharmaceutically acceptable acid addition salts thereof.

7. A compound according to claim 1 in which R is cyclobutylmethyl, R is methyl, R is hydrogen and R is methyl, said compound being N cyclobutylmethyl- A dihydronorthebainone enol methyl ether, and pharmaceutically acceptable acid addition salts thereof.

8. A compound according to claim 1 in which R is 3,3 dimethylallyl, R is methyl, R is hydrogen and R is methyl, said compound being N 3,3 dimethylallyl- A dihydronorthebainone enol methyl ether, and pharmaceutically acceptable acid addition salts thereof.

9. A compound according to claim 1 in which R is allyl, R is methyl, R is hydrogen and R is methyl, said compound being N allyl A dihydronorthebainone enol methyl ether, and pharmaceutically acceptable acid addition salts thereof.

10. A compound of the formula:

H N B R20 OH OR; in which:

R is hydrogen or lower alkyl having 1 to 4 carbon atoms; and R is hydrogen or lower alkyl having 1 to 4 carbon atoms.

References Cited UNITED STATES PATENTS 2,524,856 10/1950 Schnider et a1. 260285 K 2,740,788 4/1956 Grussner et a1. 260285 3,217,006 11/1965 Sawa et a1. 260285 3,256,287 6/1966 Sawa et a]. 260285 3,285,914 11/1966 Gordon 260285 X 3,285,922 11/1966 Gates 260285 3,299,072 1/1967 Bartels-Keith 260205 DONALD G. DAUS, Primary Examiner US. Cl. X.R. 

